This research proposal seeks to establish the capacity of our newly introduced paradigm of organocascade catalysis to accomplish, with unprecedented levels of efficiency, the total synthesis of an array of complex, natural product-based molecules. The current prevailing approach to complex molecule synthesis, generally adopted by both academic and pharmaceutical practitioners of the field, entails a 'stop-and-go'strategy, wherein each individual chemical transformation is executed as a separate process. Because of the requirement for isolation and purification of intermediates at each stage along the synthetic route, this classical approach to multi-step synthesis suffers from a number of serious limitations with regard to efficiency and product selectivity. As an alternative approach, we recently introduced a novel synthetic concept, termed organocascade catalysis, which seeks to translate some of the advantages offered by natural product biosynthesis to the realm of laboratory synthesis. Organocascade catalysis emulates the conceptual blueprint of biosynthesis through the merger of multiple sequential transformations, each governed by an orthogonal mode of organocatalytic activation, into a single cascade sequence. Toward this end, we have demonstrated, in a variety of settings, the remarkable ability of organocascade catalysis to enable the rapid conversion of simple achiral substrates to complex, stereochemically rich, single-enantiomer adducts. This research proposal seeks to demonstrate the unprecedented synthetic capabilities of organocascade catalysis through the total synthesis of a range of high-profile natural products. Due to their complexity, as well as their historical and medical significance, the natural products targeted herein serve as valuable total synthetic benchmark compounds, by which to assess the current state of the field of organic synthesis. It is of note that each of the synthetic routes to the targets proposed herein, if realizable, would represent a significant improvement, in terms of efficiency and selectivity, over previously reported total syntheses. Specifically, Project I outlines the development of an enantioselective triple organocatalytic cascade sequence. The common intermediate arising from this transformation will be rapidly advanced to key members of the Aspidosperma, Kopsia, and Strychnos families of natural products - namely, strychnine, akuammicine, kopsinine, kopsanone, aspidospermidine, and vincadifformine. Projects II and IV envision the development of second generation, quadruple cascade routes to kopsanone and strychnine, respectively. In Project III, we will pursue a rapid organocascade approach to a common intermediate en route to a number of members of the Aspidosperma and Strychnos families. The key organocascade adduct will be advanced to ochrosamine B. Project V will entail the investigation of a new cascade-based strategy toward cytotoxic teleocidin natural products, such as indolactam V, and analogs thereof. Finally, the focus of Project VI will be on the development of a SOMO-catalysis based organocascade platform, as well as the subsequent application of this novel approach to the total syntheses of the natural products, phyllantidine and bruceol.

Public Health Relevance

The objective of this research is to establish a new strategy for chemical synthesis whereby natural products, bioactive compounds and medicinal agents can be generated in a highly accelerated fashion from cheap, inexpensive and readily available starting materials.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078201-07
Application #
8302438
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (03))
Program Officer
Lees, Robert G
Project Start
2006-07-07
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
7
Fiscal Year
2012
Total Cost
$314,377
Indirect Cost
$106,477
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Horning, Benjamin D; MacMillan, David W C (2013) Nine-step enantioselective total synthesis of (-)-vincorine. J Am Chem Soc 135:6442-5
Laforteza, Brian N; Pickworth, Mark; Macmillan, David W C (2013) Enantioselective total synthesis of (-)-minovincine in nine chemical steps: an approach to ketone activation in cascade catalysis. Angew Chem Int Ed Engl 52:11269-72
Allen, Anna E; Macmillan, David W C (2012) Synergistic Catalysis: A Powerful Synthetic Strategy for New Reaction Development. Chem Sci 2012:633-658
Allen, Anna E; MacMillan, David W C (2011) Enantioselective ?-arylation of aldehydes via the productive merger of iodonium salts and organocatalysis. J Am Chem Soc 133:4260-3
Harvey, James S; Simonovich, Scott P; Jamison, Christopher R et al. (2011) Enantioselective ýý-arylation of carbonyls via Cu(I)-bisoxazoline catalysis. J Am Chem Soc 133:13782-5
Jones, Spencer B; Simmons, Bryon; Mastracchio, Anthony et al. (2011) Collective synthesis of natural products by means of organocascade catalysis. Nature 475:183-8
Van Humbeck, Jeffrey F; Simonovich, Scott P; Knowles, Robert R et al. (2010) Concerning the mechanism of the FeCl3-catalyzed alpha-oxyamination of aldehydes: evidence for a non-SOMO activation pathway. J Am Chem Soc 132:10012-4
Um, Joann M; Gutierrez, Osvaldo; Schoenebeck, Franziska et al. (2010) Nature of intermediates in organo-SOMO catalysis of alpha-arylation of aldehydes. J Am Chem Soc 132:6001-5
Allen, Anna E; Macmillan, David W C (2010) The productive merger of iodonium salts and organocatalysis: a non-photolytic approach to the enantioselective alpha-trifluoromethylation of aldehydes. J Am Chem Soc 132:4986-7
Rendler, Sebastian; Macmillan, David W C (2010) Enantioselective polyene cyclization via organo-SOMO catalysis. J Am Chem Soc 132:5027-9

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